rhBMP-2 soaked Absorbable Collagen Sponge (ACS) for the treatment of Open Tibial Shaft Fractures Clinical Summary Points to consider

Clinical Summary of International Investigation

Clinical Review Study Design Effectiveness Safety

Clinical Review STUDY DESIGN Confounding Variables Patient Assessment Study Endpoints Data Analysis

Confounding Variables Technique for IM nail insertion All fracture types considered equal Isolated fractures grouped with multiple injuries Gustilo I ≠ Gustilo II ≠ Gustilo IIIA Not all patients received a full sponge to the fracture site Large centers ≠ small centers

Distribution of Patients by Country Country# sites Control.75 mg/ml 1.5 mg/ml Total Australia Belgium/ Netherlands Canada France Germany Israel Finland/ Norway So.Africa U. K TOTALS

Clinical Aspects of Pooling Multiple centers Over 50% of patients from 2 countries Different experiences: Few patients from many sites pooled with many patients from few sites Different philosophies regarding optimal treatment : reamed vs. unreamed nails Different interpretations of healing, delayed healing Cultural and Geographic differences Applicability to US trauma populations

Assessment Methods Clinical  Fracture site tenderness  Radiographic union  Weight bearing status Independent Radiographic

Patient Assessment PAIN No scale used for comparison Differentiation between fracture site tenderness and soft tissue injury difficult

Criteria For Radiographic Union for Independent Radiology Panel A fracture was considered united when: 3 of 4 cortices demonstrated cortical bridging and/or complete disappearance of fracture lines This definition includes: 3 of 4 cortices demonstrate bridging 3 of 4 cortices demonstrated disappearance of fracture lines 2 of 4 cortices demonstrate cortical bridging and at least 1 of the remaining 2 cortices demonstrate disappearance of fracture lines 1 of 4 cortices demonstrated cortical bridging and at least 2 of the remaining 3 cortices demonstrated disappearance of fracture lines

Independent and Investigator Review Gustillo Grade IIIA Unreamed locked nail 0.75 mg/ml rhBMP

Definitions Healed Fracture: Absence of tenderness upon manual palpation of the fracture site Radiographic fracture union as assessed by the investigator Full weight bearing status

Definitions Delayed Union: “A fracture is considered a delayed union if insufficient fracture healing was observed as determined by the investigators radiographic and clinical assessment”

Number of Patients with SI recommended & Patients meeting criteria of Delayed union SOC Total Total w/SI # of criteria met 3 criteria (26%) 2 criteria (52%) 1 criterion (23%)

Primary Endpoint Secondary Interventions : How was the decision made?

Study Design: Control Group What is the standard of Care? Depends on  Fracture type  Injury severity  Bone loss  Contamination  Concomitant injuries Different prognoses for different types

Relevance of Endpoints Primary Endpoint Rate of Secondary Interventions –Recommended & Performed –Recommended & Not Performed –Not Recommended but Performed –Self Dynamizations (screw breakages) Secondary Endpoints Healing rate at 6 months 50% probability of healing CCRE

What is important? How many healed? What is the incidence of nonunion? What are the complications and incidence? Incidence of Infection? Time to healing for majority of the patients?

Combined Clinical & Radiographic Endpoint (CCRE) Independent review paired with investigator review Clinical assessment compared to purely radiographic assessment Patients with SI evaluated differently than patients without SI

Treatment of Missing Data Inconsistent Three examples

The Dilemma Investigators unblinded Investigators determined pain, weight bearing status and radiologic healing Investigators determined when to perform secondary intervention The CCRE is 50% dependent on investigators determination

The Dilemma No time course/interval to delineate “delayed healing” from “healing” No radiographic/clinical criteria to separate healing fracture vs. delayed healing How patients with delayed healing fractures were recommended for secondary intervention is imprecise. Extent to which all the investigators used the same criteria for determining a secondary intervention is unknown

Results Effectiveness Primary Endpoint Rate of Fracture Healing Time to event Analysis Probability of 50% healing Nonunion

Primary Endpoint Standard of Care 0.75 mg/ml rhBMP-2/ ACS group 1.5 mg/ml rhBMP-2/ ACS group SI66 (44%) 51 (35%) 38 (26%) Recommended & Performed 38 (25%) 25 (17%) 19 (13%) Exclude Self dynamization 31%25%21% No SI84 (56%) 98 (65%) 111 (74%)

Rate of Fracture Healing InvestigatorRadiology Panel SOC0.75 mg/ml 1.5 mg/ml SOC0.75 mg/ml 1.5 mg/ml 26 wks 36 %40 %55 %20 %25 %33 % 39 wks 48 %51 %64 %38 %41 %50 % 50 wks 51 %58 %70 %47 %52 %64 %

Probability of a Fracture Healing by Investigator

Time To Healing by Investigator TreatmentDays to HealingProbability of Healing Standard of Care14125% 18450% 27575% 0.75 mg/ml rhBMP- 2/ACS 12825% 18750% 27375% 1.5 mg/ml rhBMP- 2/ACS 10225% 14750% 27375%

Time to Independent Radiographic Assessment of Fracture Union

Time to Fracture Healing by Independent Radiology Panel TreatmentDays to HealingProbability of Healing Standard of Care18925% 27550% 35175% 0.75 mg/ml rhBMP- 2/ACS 18625% 27250% 35175% 1.5 mg/ml rhBMP- 2/ACS 18225% 27150% 35375%

Nonunion SOC0.75 mg/ml 1.5 mg/ml InvRadInvRadInvRad Overall 12 months 49%53%42%48%30%38% Patients w/ SI 12%9%13%

Time to Fracture healing by Investigator Assessment : Patients with Secondary Interventions

Safety Serology Anti-rhBMP antibodies Anti Type I Bovine collagen antibodies Hardware failure Laboratory Results Heterotopic Ossification Infection

Serology Antibodies formed to: Standard of Care 0.75 mg/ml rhBMP- 2/ACS 1.5 mg/ml rhBMP- 2/ACS rhBMP-2 1 (1%) 3 (2%) 9 (6%) Bovine Type I Collagen 9 (6%) 22 (16%) 29 (20%)

Hardware Failure SOC.75 mg/ml1.3 mg/ml Total Patients 32 (22%)25 (17%)16 (11%) Total Events Nail breakage 020 Screw Breakage Pts reamed Nail screw breakage 7/39 (18%) 8/48 (17%) 2/59 (3.4%) Pts unreamed nail screw breakage 25/108 (23%) 17/97 (18%) 14/86 (16%)

Laboratory results Liver function Tests elevated in rhBMP-2 treated groups Elevated Amylase Hypomagnesemia

Heterotopic Ossification SOC0.75 mg/ml1.5 mg/ml Patients458 Hypertrophic Callus 321 Soft tissue callus012 HO of tibia fracture 010 Synostosis101

Infection Rate SOC.75 mg/ml1.5 mg/ml Total30%23%25% Leg/Tibia29%25%24% Gustilo I18%17%19% Gustilo II20%19%20% Gustilo IIIA/B 48%30%33%

CONCLUSIONS Definitions for assessment unclear Assessments based on investigators Clinical relevance of endpoints Control group as standard of care an issue Pooling across different sites and applicability to US population an issue Outcomes Interpretations differ Safety questions